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A Strange Cancer in Animals That Broadens Our Understanding of Cancer Biology

by Anna Lau, PhD, Medical Writer

We generally think about cancer as a disease of individuals, but doing so could limit our view of cancer biology and prevents us from appreciating the complexity of this disease. Cancer can also be a disease of families. There are numerous heritable genetic mutations that greatly predispose families to the development of certain cancers (see here, here, and here).

What if cancer were a disease of a species, a contagious disease that could be passed from person to person through contact? Thankfully, human cancer is not usually contagious—but such cancer is not unheard of. There have been cases of direct transmission of cancer between people (passed between individuals through physical contact): from mother to fetus, from fetus to fetus between twins, and from organ or stem cell donor to recipient via the donated tissue. Let it be clearly emphasized that these are rare events. Thus far, no human cancer has developed the capacity to be easily transmitted through direct contact.

There are certain cancers that can be spread from person to person through an infectious agent, like a virus. The human papillomavirus can be transmitted through sexual contact and cause many kinds of cancers in both men and women. But this does not mean that the cancer itself is the contagion, only the virus.

But there are examples in the animal kingdom of contagious cancers that are directly transmissible. One is extraordinarily old, the other quite new, and appreciating their differences and similarities to human cancers can broaden our total understanding of cancer biology.

Devils die, but dogs defy a dreaded disease.

Around 1996, researchers discovered a cancer decimating the Tasmanian devil population. The cancer, termed Tasmanian devil facial tumor disease (DFTD), arose from a single clonal cell lineage in a single devil, but the cancer has spread like wildfire. Symptoms start as lesions on the face, neck, and mouth of affected animals, then enlarge (>3 cm diameter) and ulcerate. Death ensues within months of initial appearance of lesions. Since the emergence of DFTD, the devil population has been devastated, putting the animals at risk of local extinction within just a few decades! Transmission of DFTD occurs through direct contact between animals, during which tumors are transmitted as allografts that are genetically distinct from their hosts. In other words, the cancer is physically passed from one devil to another through normal contact, the cancers examined from different devils are genetically identical (ie, clonal), and the cancers are able to thrive—that is, they do not provoke a host immune response.

Figure 1. Tasmanian devil with facial tumor disease. Photo by: Menna Jones (creativecommons.org/licenses/by/2.5), via Wikimedia Commons.

Tasmanian devil with facial tumor disease. Photo by: Menna Jones (creativecommons.org/licenses/by/2.5), via Wikimedia Commons.

There is another clonally transmissible cancer that affects dogs, called canine transmissible venereal tumor (CTVT). CTVT is highly prevalent among dogs living in tropical and subtropical urban environments. Genome sequencing studies have confirmed the clonality of two CTVT tumors from dogs on distant continents and showed this cancer to be the oldest known somatic cell lineage. According to this research, CTVT arose in an ancient wolf or dog about 11,000 years ago and has been passed from dog to dog as allografts ever since then. (One can only imagine what a long, strange trip that has been.) Unlike DFTD, however, CTVT is rarely fatal. Once transferred to a new host, CTVT undergoes an initial progressive phase, marked by rapid tumor growth generally lasting for weeks, then enters a stable phase of slower tumor growth lasting from weeks to indefinitely, and finally settles into a regression phase in most dogs, during which tumors shrink and disappear. In other words, the canine immune system can overcome CTVT.

Figure 2. Dog genitals with transmissible venereal tumor.  Spugnini EP, et al. J Exp Clin Cancer Res. 2008;27:58.

Dog genitals with transmissible venereal tumor. Spugnini EP, et al. J Exp Clin Cancer Res. 2008;27:58.

DFTD and CTVT are strange, but they share properties with human cancers.

For DFTD and CTVT to propagate, they must (a) have a route of transmission, (b) survive and thrive in a new environment, and (c) evade the host immune system in the new location (at least for a period). Notably, these are requirements that human cancer cells also must meet to metastasize. Recent studies show how DFTD evades the host immune system with a strategy something like getting past a doorman. DFTD suppresses antigen presentation—it doesn’t announce itself or sign in at the “front desk”—so the “doorman” doesn’t know that DFTD has entered. CTVT does something similar, except that it suppresses antigen presentation only at first, during the progressive phase; during the stabilization and regression phases, antigen presentation is largely restored.

Suppression of antigen presentation is a tactic that human cancer cells use to evade detection when they metastasize from a primary to a secondary tumor site. What we know about CTVT suggests that restoring antigen presentation could reestablish disease control. At present, a number of agents that can bolster antigen presentation are under investigation for the treatment of human cancer. Such an immunotherapeutic approach could work, but the jury is still out.

It has also been shown that telomere length in DFTD cells is regulated. In simple terms, telomeres are to chromosomes what aglets (the protective tips) are to shoelaces; telomeres protect chromosome ends from damage, such as degradation or aberrant fusions with other chromosomes. Telomere length correlates with replication potential: the longer the telomeres, the more times a cell can divide. Telomeres in DFTD cells aren’t longer than those in normal Tasmanian devil cells, but they can be elongated when they get too short. (Imagine replacing an aglet when it starts to wear out.) Furthermore, telomere length in DFTD cells appears to be stabilized by a protective protein complex. (Imagine also wrapping an aglet in duct tape after replacement.) In human cancers, aberrant telomere homeostasis is a common feature. Efforts are underway to target telomerase, the enzyme responsible for lengthening short telomeres, as one approach to fight cancer.

What are the implications of unusual animal cancers for human cancer biology?

The existence of clonally transmissible cancers means that cancer can be a disease of a species. One could argue that such a cancer arose in Tasmanian devils because they are highly inbred and genetically similar. But such a cancer also arose in and spread successfully among genetically diverse canine breeds, suggesting that susceptibility of a species to this type of cancer is not restricted to those that are inbred. At present, it’s not known how DFTD or CTVT originally arose, or what specific mutations conferred their capacity to thrive in this unusual way, so it’d be pure speculation whether this could happen in another animal species, including humans. But considering that the clonally transmissible cancers and human cancers share common escape and survival mechanisms, we speculate that it is possible, although highly unlikely (since this has only arisen twice so far in the known history of human and animal disease studies). We don’t fully understand yet how most dogs are able to keep this cancer in check, but that they do is evidence of the strength and plasticity of the immune system. By investigating the origins of these cancers, observing their evolution, and understanding their interactions with their respective hosts, we can gain a broader view of cancer biology and how we can fight it better in humans.

The capacity of clonal cancer cells to be passed through a species attests to the awesome power of natural selection, which has led these cancers to evolve to be fit enough to survive for millennia. Sure, there are any number of organisms that have been around for at least that long, but the clonal cancers survive without sexual reproduction, an important mechanism used by many species to mix genes in new combinations. In some ways, we can liken these clonal cancers to an asexually reproducing organism, in which offspring are clones of the parent.

The future of the devils hangs in the balance.

From an evolutionary standpoint, it doesn’t benefit the DFTD cancer to kill off its host too quickly or completely, because then it too would perish. Extrapolating from the CTVT experience, it’s conceivable that DFTD and the devil could co-evolve to balance tumor growth with suppression by the host immune system. Given enough time, this could happen… but the Tasmanian devils’ advocates aren’t waiting for nature to run its course; they’re already working on a vaccine. Let’s hope investigators make it in time to save the devils.

Here’s how you can help.


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Why Wolverine Will Never Get Cancer

by Alison Wagner, PhD, Medical Writer

Wolverine?

Not this one. (WikiCommons)
Not this one. (photo from the National Park Service, accessed from WikiCommons)
This one! (Alison Wagner)
This one!
(photo by Alison Wagner)

 

 

 

 

 

 

 

 

 

An episode of the TV series The Big Bang Theory featured its lovable group of “nerds” debating who was the bravest character in the Marvel Universe. The know-it-all Sheldon proposed that whoever had to give Wolverine a prostate exam was, indeed, the winner of that dubiously enviable title. Sheldon’s wrong on this one, though, and comic book urologists can relax – Wolverine won’t need the prostate exam.

Wolverine’s primary mutant power is his healing ability.* Healing is a job regulated by the immune system, so we can assume that Wolverine’s immune system is phenomenal, given his healing ability and his resistance to aging and illness. It is this superb immune system that will prevent a future storyline wherein Wolverine deals with a cancer diagnosis.

*Yes, Wolverine also has other mutant abilities, and his claws are awesome. However, without his healing ability, he would not have been able to tolerate the process of fusing “adamantium” to his bones, and the claws would then have remained bone claws and not the super-cool blades that are so emblematic of Wolverine.

The immune system, the body’s major defense system, is intimately involved in cancer. The two major arms of the immune system are the adaptive immune system, including T and B cells that can be considered the “special teams,” and the innate immune system, which is more like the ground troops. The ability to avoid adaptive response is a key feature of the success of cancerous cells. Were our immune systems as excellent as Wolverine’s, our adaptive immune systems would seek out and demolish cancer before it could take hold. Failure of the adaptive immune system to control cancerous cell growth is a phenomenon that has long interested researchers, and advances in that area are discussed in this excellent post by Heather. In essence, Wolverine’s immune response is what we aspire to achieve in the field of immuno-oncology by promoting T-cell activation and targeting of cancer cells.

Advances in immuno-oncology deal mostly in the adaptive immune system (T and B cells); however, the innate immune system plays an even more active role in tumor development. For decades, tumors have been described as “wounds that do not heal.”** Under normal circumstances, the presence of a wound activates the innate immune system, causing leukocytes such as macrophages to quickly migrate to the site of the wound and begin their work of healing. The healing process requires activation of these cells, initiating reparative processes including inflammation and angiogenesis – two key processes also seen in tumor microenvironments. The key difference between wound healing and cancer is that in time, wounds heal and activation and inflammation are resolved, allowing the immune cells to disperse away from the site, and everything returns to normal.

**Clearly, “wounds that do not heal” are an impossibility for Wolverine, who has survived grievous wounds and even being torn in half!

Cancer does not resolve. In cancer, the immune cells do not disperse. In fact, after the initial migration to the tumor cells, they are overwhelmed by inhibitory signals from the tumor cells that alter the the immune cells’ activation state. This reduces cell killing and instead tricks the immune cells into providing pro-growth cytokines*** that actually help the cancer cells proliferate, create new blood vessels, and invade new tissue. These immune cells not only do not destroy the tumor cells – they actively contribute to the microenvironment that helps to sustain and grow tumors. If the immune system is  the military of the body, the troops go in to do their job against the enemy (the cancer), but are then brainwashed and forced into supportive roles by that same enemy.

***The immune system is enormously complex. Cytokines can be pro-inflammatory, pro-growth, anti-inflammatory, anti-growth, and so on. to Add to the confusion, the same cytokines can have opposite effects under different circumstances, not all of which we understand. Macrophages in particular have different states of activation, which are still controversial, and produce different sets of cytokines depending on the state. There is even a still-debated state specific to the tumor microenvironment. We have a lot to learn!

This would never happen to Wolverine. With his supercharged immune system, cancer cells would be obliterated immediately and efficiently, the tumor’s inhibitor signals unheeded. His mutant power would protect him from the immune dysfunctions that we mere humans suffer in our fight against cancer. However, we’re catching up. The immune system remains somewhat of a mystery, our knowledge of it lagging behind that of other biological systems. But promising advances such as those in immunotherapy are revealing more and more how we might manipulate it to maybe, possibly, be just a little more like Wolverine.

Now, who wants to work on the adamantium claws?


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Breakthrough of the Year – Cancer Immunotherapy?

By Heather Lasseter, PhD, Medical Writer

Are advances in cancer immunotherapy a top scientific achievement of the year? 

Editors of Science certainly think so, heralding “cancer immunotherapy” as 2013’s Breakthrough of the Year: “This year marks a turning point in cancer, as long-sought efforts to unleash the immune system against tumors are paying off – even if the future remains a question mark.”

Picture4

Awareness ribbons representing lung, breast, cervical, brain, kidney, prostate, and colon cancer, and melanoma (adapted from MesserWoland, wikimediacommons.org).

With June as Cancer Immunotherapy Month (designated by the Cancer Research Institute), cancer immunotherapy is a hot topic in oncology – especially as research here may lead to major treatment breakthroughs for many cancers. But currently approved treatment comes with a hefty price tag: approximately $120,000 for a round of therapy. Given the potentially modest impact on survival (for instance, on the order of several months), does cancer immunotherapy truly represent a key breakthrough of 2013?

 

Immune destruction – a hallmark of cancer

Hallmarks

Hanahan and Weinberg’s hallmarks of cancer (Cell. 2011;144:646-674).

Avoiding immune destruction was recognized as one of the emerging hallmarks of cancer by Hanahan and Weinberg in 2011. Cancer cells survive and thrive through their well-known characteristics of ceaseless proliferation and invasion, as well as their ability to  evade the body’s natural defenses. While the immune system is tasked with cleaning up cells gone rogue, cancer cells not only escape these defense mechanisms, but hijack the immune system for their own advantage (i.e., tumor angiogenesis).

Cancer immunotherapy – the idea of targeting the body’s own immune system to attack cancerous cells – has been around for about 20 years. But with poor understanding of mechanisms for immune activation and hesitancy from pharmaceutical companies, cancer immunotherapy has only recently gained traction.

Early work by cancer immunologist James Allison (published in Science in 1996) sparked the renaissance in cancer immunotherapy. He demonstrated that administering antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4) in vivo caused the rejection of tumor cells. However, it was not until 15 years later that ipilimumab – a monoclonal antibody that targets CTLA-4 on T cells – became the first immunotherapy approved for treating metastatic melanoma. While cancer cells release antigens that activate the immune system, they also produce proteins that bind to CTLA-4, thereby preventing a full-out immune attack. Ipilimumab blocks this inhibitory signal, letting the immune system do its job. The result: cancer cell death.

Clinical trials are currently underway to assess efficacy of ipilimumab and other agents targeted to  reverse immune checkpoint pathways, which cancer cells exploit to inhibit the immune system. These are being assessed in the treatment of melanoma, lymphoma, lung, breast, gastric, and prostate cancers. Such agents include antibodies against programmed death-1 (PD-1), a molecule on T cells that puts the brakes on T-cell activation. Moreover, combination therapy of an anti-CTLA-4 plus anti-PD-1 has produced a “rapid and deep tumor regression” in patients with advanced melanoma, according to a study published in the New England Journal of Medicine. In addition, more recent advances involve genetically engineering T cells to express chimeric antigen receptors (CARs). CARs permit T cells to specifically target antigens on tumor cells.

One exciting possibility may be personalized immunotherapy

In a recent study in Science, CD4+ T helper cells were identified that responded to a mutated antigen found in the cancer cells of a patient with metastatic epithelial cancer. These mutation-reactive immune cells were extracted, amplified in cell cultures, and transfused back to the patient using a technique called adoptive cell transfer. The results were remarkable: the tumor regressed and then stabilized until 13 months post-transfusion. Following disease progression and a second round of immunotherapy, the tumor again regressed (last follow-up of 6 months).

Adoptive T-cell therapy (Simoncaulton, wikimediacommons.org).

Broadening the cancer immunotherapy pool

In the last several years, many groups have launched themselves into this line of research. As part of its Moon Shots Program, the University of Texas MD Anderson Cancer Center has collaborated in 2014 with four large companies – Johnson & Johnson, Pfizer, GlaxoSmithKline, and AstraZeneca’s MedImmune – to accelerate the development of immunotherapies and reduce cancer deaths. And cancer immunotherapy was a hot topic at the ASCO Annual Meeting, with large pharmaceutical companies sharing promising clinical data:

  • Bristol-Myers Squibb: Combination of the PD-1 immune checkpoint inhibitor nivolumab plus ipilimumab in a phase 1b trial shrank tumors in 42% of patients with advanced melanoma and produced 1- and 2-year overall survival of 85% and 79%, respectively.
  • Merck: In a phase 1b trial, the anti-PD-1 antibody pembrolizumab (MK-3475) reduced tumors in 51% of patients with PD-ligand 1 (PD-L1)-positive advanced head and neck cancer and produced a best overall response rate (ORR) of 20%.
  • RocheIn a phase 1 trial, the anti-PD-L1 therapy MPDL3280A shrank tumors in 43% of patients with PD-L1-positive metastatic bladder cancer and produced an ORR of 52%.
  • AstraZeneca: Although the clinical data were limited, AstraZeneca described the phase 1 dose-escalation trial assessing the PD-L1 inhibitor MEDI-4736 plus CTLA-4 inhibitor tremelimumab in patients with advanced solid tumors.

Moving cancer immunotherapy forward

While these results are promising, cancer immunotherapy only benefits a certain population of patients – and the reasons why are poorly understood. For instance, treatment efficacy may be impaired by the presence of mutations in a patient’s tumor that confer protection against antitumor immunity. As stated by Tjin et al in Cancer Immunology Research, “Immunotherapy is a promising strategy… but the modest clinical responses so far call for improvement of therapeutic efficacy.”

So what’s next for cancer immunotherapy?

It will be necessary to develop biomarkers for patients who will show a clinical benefit, increase the proportion who respond to treatment, and develop more potent treatment strategies. Treatment strategies will likely involve combination therapies, adding an immune system booster, and streamlining the development of targeted treatments. Progress to broaden and optimize the benefits of cancer immunotherapy is needed to make it worthy of being called the “Breakthrough of the Year.”

 

 

 

 


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Should the “Gold Standard” Be the Old Standard? A New Approach to Randomized Clinical Studies

By Anna Lau, PhD, Medical Writer

From 1975 to 2005, the average cost to develop a single new drug rose from $100 million to $1.3 billion (adjusted to year 2000 US dollars). At least 90% of this staggering cost is consumed by executing phase 3 clinical studies. But as phase 3 studies have gotten larger, longer, and more complex, fewer patients meet the eligibility criteria and more participants quit mid-study. In addition, about 70%-75% of drugs fail this phase of development because of safety concerns, lack of efficacy, or other reasons. No wonder there’s frustration!

Is it time to change the way phase 3 studies are conducted?

Conventional phase 3 studies are usually randomized and controlled. The salient study design feature is the equal probability that participants will be randomized to intervention or control. This randomization scheme minimizes selection bias more effectively than any other study design element, making it the “gold standard” of study designs.

__________

Although phase 3 randomized studies assume a priori that the null hypothesis is true (that the intervention and the control are equal), patients generally assume that the intervention is superior to control. What do you think is the basis for this bias that “new is better”?

__________

But this randomization element is precisely why up to 31% of patients decline to participate in clinical studies. Clinical investigators could opt for a 2:1 randomization ratio, but this would only increase the odds of—not guarantee—assignment to the intervention arm. Also, if a two-arm randomized controlled study shows no advantage of intervention over control, then it’s back to the drawing board to plan a brand new study protocol, a process that could take years. What’s the alternative?

Enter the outcome-adaptive randomization study design.

With outcome-adaptive randomization, randomization probabilities can be adjusted based on experimental results already observed—in other words, patients are more likely to be assigned to the more effective study arm (if there is one) over the course of the study (Figure 1).

study designFigure 1. Diagrammatic representation of fixed and outcome-adaptive randomization schemes. *Probability of assignment to intervention arm = [(probability that intervention is superior)a] ÷ [(probability that intervention is superior)a + (probability that control is superior)a], where a is a positive tuning parameter that controls the degree of imbalance (a is usually a value between 0 and 1; when a = 0, randomization is fixed at 1:1; when a = 1, the probability of randomization to intervention equals the probability that intervention is superior). Whew! That’s enough math.

Outcome-adaptive randomization study design is based on Bayesian analysis, an inductive approach that uses observed outcomes to formulate conclusions about the intervention. For example: Given the observed experiment results, what is the probability that intervention is superior to control? In contrast, a classical statistical analysis uses deductive inference to determine the probability of an observed outcome assuming that the null hypothesis is true. For example: What is the probability of observing these experimental results, if the intervention and the control are equally effective?

So, outcome-adaptive randomization must be better for patients, right?
Short answer: not always.

In a recent report, Korn and Friedlin used simulations to compare fixed balanced randomization (1:1) and outcome-adaptive randomization. The authors assumed: (1) there are two study arms, one of which is a control arm; (2) outcomes are short-term; (3) outcomes are binary (response vs. no response); and (4) patient accrual rates are not affected by study design. The authors determined the required sample sizes, and average proportions of patients with response to treatment (responders) and numbers of patients without response to treatment (nonresponders), assuming a 40% response rate with intervention vs. 20% response rate with control. They found that the adaptive design did not markedly change the proportion of responders but increased the number of nonresponders, compared with 1:1 randomization design. The authors found outcome-adaptive randomization to be “inferior” to 1:1 randomization and to offer “modest-to-no benefits to the patients.”

What?!

These results may seem surprising, but there are general downsides to outcome-adaptive randomization:

  • Adaptive randomization studies are logistically complicated. For instance, they require that treatment assignment be linked to outcome data.
  • Early results from the study could bias enrollment into the study. For instance, would patients enroll in a study in which control looks better than intervention?
  • If control does outperform intervention, the study sponsor might end up funding a study in which the majority of patients are assigned to the control arm.

But there must be upsides! And indeed there are.

First, the assumptions made by Korn and Friedlin (only two study arms, patient accrual rates not affected by study design, etc), limit the applicability of their conclusions to situations outside the described scenarios (full description of limitations here).

Further, the advantages of this design are highlighted in studies with more than two arms (eg, multiple regimens, doses, or dosing schedules). In these, a superior intervention could be identified without enrolling equal numbers of patients in each arm. This could allow shorter clinical studies that evaluate more interventions. And if one arm performs poorly, randomization to that arm could be limited or the arm could be dropped altogether, depending on the inferiority cutoffs built into the study design. Furthermore, outcome-adaptive randomization combined with biomarker studies at baseline can potentially identify relationships between response and biomarker status, which cannot be achieved with fixed randomization.

Take the phase 2 BATTLE study, the first completed prospective, outcome-adaptive, randomized study in late-stage non-small cell lung cancer. Patients underwent tumor biomarker profiling before randomization to one of four treatment arms: erlotinib, sorafenib, vandetanib, and erlotinib + bexarotene. Subsequent randomization considered the responses of previously randomized patients with the same biomarker profile. Historically, the disease control rate (DCR) at 8 weeks for this patient population is about 30%. But in BATTLE, overall DCR was 46%. Even better, the study showed that biomarker profile correlates with response to specific treatments. This was important because, at the time, biomarkers for those drugs had not been validated. Overall, BATTLE demonstrated the possibility and feasibility of personalizing treatment to patient.

Right now, the phase 2 I-SPY 2 study is trying to do for breast cancer what the BATTLE study did for lung cancer. In I-SPY 2, newly diagnosed patients with locally advanced breast cancer will undergo biomarker profiling before randomization to one of up to 12 neoadjuvant therapy regimens. The study design will allow clinical investigators to graduate (move forward in development when outcome fulfills a Bayesian prediction), drop, or add drugs seamlessly throughout the course of the study without terminating the study and starting over. This could drastically reduce the time it takes the study to move from one drug to another.

Should outcome-adaptive randomization become the new “gold standard”?

Short answer: Not quite yet. But the potential advantages and disadvantages of these study designs must be recognized. Based on the attention that the BATTLE and I-SPY 2 studies have gotten, though, expect to see more outcome-adaptive randomized studies in the future. The potential for shorter clinical studies evaluating more than one intervention at a time could mean considerable cost and time savings in drug development.